tbuckley/cabot-search huggingface dataset:
The Vexing Problem of Preterm Birth Prevention
Authors: Donald J. Dudley, Christopher S. Ennen
Journal: JAMA (2023)

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EYA2 tyrosine phosphatase inhibition reduces MYC and prevents medulloblastoma progression
Authors: Arthur R Wolin, Melanie Y Vincent, Taylor Hotz, Stephen C Purdy, Sheera R Rosenbaum, Connor J Hughes, Jessica Y Hsu, Michael U J Oliphant, Brock Armstrong, Veronica Wessells, Marileila Varella-Garcia, Matthew D Galbraith, Angela Pierce, Dong Wang, Sujatha Venkataraman, Etienne Danis, Bethany Veo, Natalie Serkova, Joaquin M Espinosa, Daniel L Gustafson, Rajeev Vibhakar, Heide L Ford
Journal: Neuro-Oncology (2023)

Abstract Background Medulloblastoma is the most common pediatric brain malignancy. Patients with the Group 3 subtype of medulloblastoma (MB) often exhibit MYC amplification and/or overexpression and have the poorest prognosis. While Group 3 MB is known to be highly dependent on MYC, direct targeting of MYC remains elusive. Methods Patient gene expression data were used to identify highly expressed EYA2 in Group 3 MB samples, assess the correlation between EYA2 and MYC, and examine patient survival. Genetic and pharmacological studies were performed on EYA2 in Group 3 derived MB cell models to assess MYC regulation and viability in vitro and in vivo. Results EYA2 is more highly expressed in Group 3 MB than other MB subgroups and is essential for Group 3 MB growth in vitro and in vivo. EYA2 regulates MYC expression and protein stability in Group 3 MB, resulting in global alterations of MYC transcription. Inhibition of EYA2 tyrosine phosphatase activity, using a novel small molecule inhibitor (NCGC00249987, or 9987), significantly decreases Group 3 MB MYC expression in both flank and intracranial growth in vivo. Human MB RNA-seq data show that EYA2 and MYC are significantly positively correlated, high EYA2 expression is significantly associated with a MYC transcriptional signature, and patients with high EYA2 and MYC expression have worse prognoses than those that do not express both genes at high levels. Conclusions Our data demonstrate that EYA2 is a critical regulator of MYC in Group 3 MB and suggest a novel therapeutic avenue to target this highly lethal disease.
Anakinra‐Associated Systemic Amyloidosis
Authors: Sara Alehashemi, Surendra Dasari, Anvitha Metpally, Kat Uss, Leslie A. Castelo‐Soccio, Theo Heller, Peter Kellman, Marcus Y. Chen, Mark Ahlman, Jeff Kim, Susannah Wargo, Douglas B. Kuhns, Danielle Fink, Adriana de Jesus, Paul S. Martin, Richard Chang, Jonathan Bolanos, Chyi‐Chia Richard Lee, Samih H. Nasr, Raphaela Goldbach‐Mansky, Ellen McPhail
Journal: Arthritis & Rheumatology (2023)

Objective To describe a 41‐year‐old woman with a history of neonatal onset multisystem inflammatory disease, on treatment with daily subcutaneous injections of 600 mg of recombinant interleukin‐1 receptor antagonist (IL‐1Ra) protein, anakinra, since the age of 28, who presented with golf‐ball size nodules at the anakinra injection sites, early satiety, new onset nephrotic syndrome in the context of normal markers of systemic inflammation. Methods Clinical history and histologic evaluation of biopsies of skin, gastric mucosa, and kidney with Congo‐red staining and proteomic evaluation of microdissected Congo red–positive amyloid deposits by liquid chromatography‐tandem mass spectrometry. Results The skin, stomach, and kidney biopsies all showed the presence of Congo red–positive amyloid deposits. Mass spectrometry‐based proteomics demonstrated that the amyloid deposits in all sites were of AIL1RAP (IL‐1Ra protein)‐type. These were characterized by high spectral counts of the amyloid signature proteins (apolipoprotein AIV, apolipoprotein E, and serum amyloid P‐component) and the amyloidogenic IL‐1Ra protein, which were present in Congo red–positive areas and absent in Congo red–negative areas. The amino acid sequence identified by mass spectrometry confirmed that the amyloid precursor protein was recombinant IL‐1Ra (anakinra) and not endogenous wild‐type IL‐1Ra. Conclusion This is the first report of iatrogenic systemic amyloidosis due to an injectable protein drug, which was caused by recombinant IL1Ra (anakinra).
A chronic infectious bladder stone causing an obstructive emphysematous cystitis
Authors: Louis Boutin, Jeremy Zarworski, Ellie Tang, Annabelle Goujon, Benoit Plaud, Jean-Luc Donay, François Dépret, Dminique Bazin, Emmanuel Letavernier, Emmanuel Dudoignon
Journal: Clinical Microbiology and Infection (2023)
Low-Normal FVC Trajectory Starting in Early Adulthood and Risk of Future Interstitial Abnormalities
Authors: Gabrielle Y. Liu, Laura A. Colangelo, Raul San Jose Estepar, Anthony J. Esposito, Samuel Y. Ash, Bina Choi, David R. Jacobs, Mercedes R. Carnethon, George R. Washko, Ravi Kalhan
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Low-Normal FVC Trajectory Starting in Early Adulthood and Risk of Future Interstitial Abnormalities." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
The NHS at 75: let’s stand up for regaining and retaining NHS principles
Authors: Hannah D Walker
Journal: BMJ (2023)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following The NHS at 75: let’s stand up for regaining and retaining NHS principles Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Childhood-onset Erdheim-Chester disease in the molecular era: clinical phenotypes and long-term outcomes of 21 patients
Authors: Francesco Pegoraro, Martina Mazzariol, Irene Trambusti, Sameer Bakhshi, Saumyaranjan Mallick, Ira J. Dunkel, Cor van den Bos, Özlem Tezol, Shijun Shan, Suheyla Ocak, Flavio Giordano, Carmela De Fusco, Stefania Gaspari, Anna Maria Buccoliero, Maria Luisa Coniglio, Elisa Buti, Paola Romagnani, Jennifer Picarsic, Jean Donadieu, Eli L. Diamond, Jean-François Emile, Elena Sieni, Julien Haroche, Augusto Vaglio
Journal: Blood (2023)
<i>Roseburia intestinalis</i>generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8<sup>+</sup>T cells
Authors: Xing Kang, Changan Liu, Yanqiang Ding, Yunbi Ni, Fenfen Ji, Harry Cheuk Hay Lau, Lanping Jiang, Joseph JY Sung, Sunny H Wong, Jun Yu
Journal: Gut (2023)

Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy.R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in ApcMin/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling.R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in ApcMin/+ mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B+, interferon (IFN)-γ+ and tumour necrosis factor (TNF)-α+ CD8+ T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8+ T cells to induce its activity through activating nuclear factor kappa B (NF-κB) signalling.R. intestinalis protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8+ T cells. R. intestinalis is a potential adjuvant to augment anti-PD-1 efficacy against CRC.
Comparison of drugs for active eosinophilic oesophagitis: systematic review and network meta-analysis
Authors: Pierfrancesco Visaggi, Brigida Barberio, Giulio Del Corso, Nicola de Bortoli, Christopher J Black, Alexander C Ford, Edoardo Savarino
Journal: Gut (2023)

There is currently no recommendation regarding preferred drugs for active eosinophilic oesophagitis (EoE) because their relative efficacy is unclear. We conducted an up-to-date network meta-analysis to compare proton pump inhibitors, off-label and EoE-specific topical steroids, and biologics in EoE.We searched MEDLINE, Embase, Embase Classic and the Cochrane Central Register of Controlled Trials from inception to June 2023. We included randomised controlled trials (RCTs) comparing efficacy of all drugs versus each other, or placebo, in adults and adolescents with active EoE. Results were reported as pooled relative risks with 95% CIs to summarise effect of each comparison tested, with drugs ranked according to P score RESULTS: Seventeen RCTs were eligible for systematic review. Of these, 15 studies containing 1813 subjects with EoE reported extractable data for the network meta-analysis. For histological remission defined as ≤6 eosinophils/high-power field (HPF), lirentelimab 1 mg/kg monthly ranked first. For histological remission defined as ≤15 eosinophils/HPF, budesonide orally disintegrating tablet (BOT) 1 mg two times per day ranked first. For failure to achieve symptom improvement, BOT 1 mg two times per day and budesonide oral suspension (BOS) 2 mg two times per day were significantly more efficacious than placebo. For failure to achieve endoscopic improvement based on the EoE Endoscopic Reference Score, BOT 1 mg two times per day and BOS 1 mg two times per day or 2 mg two times per day were significantly more efficacious than placebo.Although this network meta-analysis supports the efficacy of most available drugs over placebo for EoE treatment, significant heterogeneity in eligibility criteria and outcome measures among available trials hampers the establishment of a solid therapeutic hierarchy.
Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy
Authors: Sophie Karolczak, Ashish R. Deshwar, Evangelina Aristegui, Binita M. Kamath, Michael W. Lawlor, Gaia Andreoletti, Jonathan Volpatti, Jillian L. Ellis, Chunyue Yin, James J. Dowling
Journal: Journal of Clinical Investigation (2023)

X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, 4 patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized what we believe to be a novel liver phenotype in a zebrafish model of this disease. Specifically, we found that loss-of-function mutations in mtm1 led to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosome-mediated trafficking of canalicular transporters. Using a reporter-tagged Mtm1 zebrafish line, we established localization of Mtm1 in the liver in association with Rab11, a marker of recycling endosomes, and canalicular transport proteins and demonstrated that hepatocyte-specific reexpression of Mtm1 could rescue the cholestatic phenotype. Last, we completed a targeted chemical screen and found that Dynasore, a dynamin-2 inhibitor, was able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate, for the first time to our knowledge, liver abnormalities that were directly caused by MTM1 mutation in a preclinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.
SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations
Authors: Kuheli Banerjee, Yanzhu Lin, Johannes Gahn, Julio Cordero, Purnima Gupta, Islam Mohamed, Mariona Graupera, Gergana Dobreva, Martin A. Schwartz, Roxana Ola
Journal: Journal of Clinical Investigation (2023)

Vascular networks form, remodel and mature under the influence of both fluid shear stress (FSS) and soluble factors. Physiological FSS promotes and maintains vascular stability via synergy with Bone Morphogenic Protein 9 (BMP9) and BMP10. Conversely, mutation of the BMP receptors ALK1, Endoglin or the downstream effector SMAD4 leads to Hereditary Hemorrhagic Telangiectasia (HHT), characterized by fragile and leaky arterial-venous malformations (AVMs). But how endothelial cells (EC) integrate FSS and BMP signals in vascular development and homeostasis, and how mutations give rise to vascular malformations is not well understood. Here, we aimed to elucidate the mechanism of synergy between fluid shear stress and SMAD signaling in vascular stability and its failure in HHT. We have now found that loss of Smad4 increases ECs' sensitivity to flow by lowering the FSS set point with resulting AVMs exhibiting features of excessive flow-mediated morphological responses. Mechanistically, loss of SMAD4 disinhibits flow-mediated KLF4-TIE2-PI3K/Akt signaling leading to cell cycle progression - mediated loss of arterial identity due to KLF4-mediated repression of cyclin dependent Kinase (CDK) inhibitors, CDKN2A and CDKN2B. Thus, AVMs caused by Smad4 deletion are characterized by chronic high flow remodeling with excessive EC proliferation and loss of arterial identity as triggering events.
Infant food allergy phenotypes and association with lung function deficits and asthma at age 6 years: a population-based, prospective cohort study in Australia
Authors: Rachel L Peters, Victoria X Soriano, Kate Lycett, Catherine Flynn, Nur Sabrina Idrose, Mimi L K Tang, Rushani Wijesuriya, Katrina J Allen, Sarath Ranganathan, Adrian J Lowe, Kirsten P Perrett, Caroline J Lodge, Jennifer J Koplin, Shyamali C Dharmage
Journal: The Lancet Child & Adolescent Health (2023)
Reply to Deng-Xiong Li, De-Chao Feng, and Shi Deng’s Letter to the Editor re: Gyrithe Lynghøj Pedersen, Marie Schmidt Erikson, Karin Mogensen, Susanne Rosthøj, Gregers Gautier Hermann. Outpatient Photodynamic Diagnosis-guided Laser Destruction of Bladder Tumors Is as Good as Conventional Inpatient Photodynamic Diagnosis-guided Transurethral Tumor Resection in Patients with Recurrent Intermediate-risk Low-grade Ta Bladder Tumors. A Prospective Randomized Noninferiority Clinical Trial. Eur Urol …
Authors: Gyrithe Lynghøj Pedersen, Karin Mogensen, Susanne Rosthøj, Gregers Gautier Hermann
Journal: European Urology (2023)
High drug loading hydrophobic cross-linked dextran microspheres as novel drug delivery systems for the treatment of osteoarthritis
Authors: Zhimin Li, Xianjing Feng, Shixing Luo, Yanfeng Ding, Zhi Zhang, Yifeng Shang, Doudou Lei, Jinhong Cai, Jinmin Zhao, Li Zheng, Ming Gao
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Drug delivery via intra-articular (IA) injection has proved to be effective in osteoarthritis (OA) therapy, limited by the drug efficiency and short retention time of the drug delivery systems (DDSs). Herein, a series of modified cross-linked dextran (Sephadex, S0) was fabricated by respectively grafting with linear alkyl chains, branched alkyl chains or aromatic chain, and acted as DDSs after ibuprofen (Ibu) loading for OA therapy. This DDSs expressed sustained drug release, excellent anti-inflammatory and chondroprotective effects both in IL-1β induced chondrocytes and OA joints. Specifically, the introduction of a longer hydrophobic chain, particularly an aromatic chain, distinctly improved the hydrophobicity of S0, increased Ibu loading efficiency, and further led to significantly improving OA therapeutic effects. Therefore, hydrophobic microspheres with greatly improved drug loading ratio and prolonged degradation rates show great potential to act as DDSs for OA therapy.
High Myopia Normative Database of Peripapillary Retinal Nerve Fiber Layer Thickness to Detect Myopic Glaucoma in a Chinese Population
Authors: Yunhe Song, Fei Li, Rachel S. Chong, Wei Wang, An Ran Ran, Fengbin Lin, Peiyuan Wang, Zhenyu Wang, Jingwen Jiang, Kangjie Kong, Ling Jin, Meiling Chen, Jian Sun, Deming Wang, Clement C. Tham, Dennis S.C. Lam, Linda M. Zangwill, Robert N. Weinreb, Tin Aung, Jost B. Jonas, Kyoko Ohno-Matsui, Ching-Yu Cheng, Neil M. Bressler, Xiaodong Sun, Carol Y. Cheung, Shida Chen, Xiulan Zhang, Xiulan Zhang, Yizhi Liu, Lin Lv, David S. Friedman, Jost B. Jonas, Tin Aung, Shida Chen, Wei Wang, Fengbin Lin, Yunhe Song, Peiyuan Wang, Fei Li, Kai Gao, Bingqian Liu, Yuhong Liu, Meiling Chen, Neil M. Bressler, Ki Ho Park, Dennis S.C. Lam, Mingguang He, Kyoko Ohno-Matsui, Robert N. Weinreb, Ching-Yu Cheng, Paul Healey, Linda M. Zangwill, Xiang Chen, Guangxian Tang, Ling Jin
Journal: Ophthalmology (2023)
Baseline Mutations and ctDNA Dynamics as Prognostic and Predictive Factors in ER-Positive/HER2-Negative Metastatic Breast Cancer Patients
Authors: Javier Pascual, Miguel Gil-Gil, Paula Proszek, Christoph Zielinski, Alistair Reay, Manuel Ruiz-Borrego, Rosalind Cutts, Eva M. Ciruelos Gil, Andrew Feber, Montserrat Muñoz-Mateu, Claire Swift, Begoña Bermejo, Jesus Herranz, Mireia Margeli Vila, Antonio Antón, Zsuzsanna Kahan, Tibor Csöszi, Yuan Liu, Daniel Fernandez-Garcia, Isaac Garcia-Murillas, Michael Hubank, Nicholas C. Turner, Miguel Martín
Journal: Clinical Cancer Research (2023)

Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy.Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model.201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms.We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.
F-18 FDG PET for Evaluation of Bone Marrow Involvement in Non-Hodgkin Lymphoma
Authors: Yen-Kung Chen, Chia-Lu Yeh, Chih-Cheng Tsui, Ji-An Liang, Jin-Hua Chen, Chia-Hung Kao
Journal: Clinical Nuclear Medicine (2011)

Background: In recent years, the use of F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has become widespread for the staging of lymphoma. In non-Hodgkin lymphoma (NHL), the bone marrow (BM) involvement is a sign of extensive disease, and the iliac crest BM biopsy (BMB) is the established method for the detection of BM infiltration. However, iliac crest BMB is associated with a high rate of false-negative results. We assess the ability of FDG PET or PET/CT scan to ascertain the presence of BM involvement in aggressive and indolent NHL. Methods: The authors conducted a systematic MEDLINE search of articles published (last update, May 2010). Two reviewers independently assessed the methodological quality of each study. A meta-analysis of the reported sensitivity and specificity of each study was performed. Results: Eight studies met the inclusion criteria. The studies had several design deficiencies. Pooled sensitivity and specificity for the detection of non-Hodgkin aggressive lymphoma were 0.74 (95% CI, 0.65–0.83) and 0.84 (95% CI, 0.80–0.89), respectively. Pooled sensitivity and specificity for the detection of non-Hodgkin indolent lymphoma were 0.46 (95% CI, 0.33–0.59) and 0.93 (95% CI, 0.88–0.98), respectively. Conclusions: The diagnostic accuracy of FDG PET or PET/CT scans was slightly higher but without significant statistical difference (P = 0.1507) in patients with non-Hodgkin aggressive lymphoma as compared with those with non-Hodgkin indolent lymphoma. The sensitivity to detect indolent lymphoma BM infiltration was low for FDG PET or PET/CT.